In this project, we elect to explore the role of gene/environment interaction by looking at environment not as the repository of noxious factors, but as the vector of complex inanimate and social stimulations. Our hypothesis is that an enriched environment incorporating social interactions, learning, and exercise modulates the effects of genetic risk factors and pathogenic mutations on the natural history of ALS. To test this hypothesis, we will use transgenic mice expressing the glycine-93 --> arginine mutant copper/zinc superoxide dismutase (SOD1G93A), a recognized model of inherited ALS, and well-validated conditions of enriched environment, which have been shown to be beneficial to a variety of pathological situations affecting the adult nervous system. Specific Aim (SA)-I will evaluate the effect of such an enriched environment on the clinical expression of the disease in transgenic SOD1G93A mice. We will determine whether transgenic SOD1G93A mice exposed to an enriched environment become symptomatic later and survive longer than their counterparts exposed to a standard environment. SA-II will elucidate the anatomical correlates of the effects provided by this enriched environment in transgenic SOD1G93A mice. Here, the status of the lower motor neuron pathway and the magnitude of the glial reaction will be compared among transgenic SOD1G93A mice exposed to different environmental conditions. SA-III will investigate the molecular basis of the effects provided by this enriched environment in transgenic SOD1G93A mice. As a first step toward this goal, protein expression profiles in spinal cords from transgenic SOD1G93A mice exposed to the different environmental conditions will be compared using proteomic approaches. This development/exploratory project offers an high-risk/high-yield set of studies which may demonstrate, in an original way, how environment may impact on the occurrence and the progression of ALS.